WO2011008597A1 - Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10 - Google Patents

Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10 Download PDF

Info

Publication number
WO2011008597A1
WO2011008597A1 PCT/US2010/041122 US2010041122W WO2011008597A1 WO 2011008597 A1 WO2011008597 A1 WO 2011008597A1 US 2010041122 W US2010041122 W US 2010041122W WO 2011008597 A1 WO2011008597 A1 WO 2011008597A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
alkoxy
heteroaryl
cycloalkyl
Prior art date
Application number
PCT/US2010/041122
Other languages
English (en)
Inventor
Ginny D. Ho
William M. Seganish
Deen B. Tulshian
Cornelis Marius Timmers
Rachel Deborah Van Rijn
Hubert Jan Jozef Loozen
Original Assignee
Schering Corporation
N. V. Organon
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corporation, N. V. Organon filed Critical Schering Corporation
Publication of WO2011008597A1 publication Critical patent/WO2011008597A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to dihydroimidazoisoquinoline derivatives, to the use of the compounds as phosphodiesterase 10 (PDElO) inhibitors for the treatment of PDElO- modulated disorders, and to pharmaceutical compositions comprising the compounds.
  • PDElO phosphodiesterase 10
  • PDElO is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehler et al, "The potential therapeutic use of phosphodiesterase 10 inhibitors", Expert Opin. Ther. Patents (2007) 17(2): 147-158.
  • PDElO is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery.
  • MSNs striatal medium spiny neurons
  • PDElO inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopallidal output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striatal output that characterizes schizophrenia.
  • PDElO inhibition should improve the cognitive dysfunction that characterizes schizophrenia.
  • the discrete localization of PDElO should lead to an improved side effect profile: typical side effects include extrapyramidal syndrome, diabetes, weight gain, hyperprolactinemia, sedation and QT C prolongation.
  • PDElO inhibitors have also been reported to be useful in treating in other CNS (central nervous system) disorders such as psychosis, cognitive disorders (such as
  • Alzheimer's disease bipolar disorder
  • depression depression
  • diet-induced obesity diabetes and metabolic syndrome.
  • Papaverine has been identified as a PDElO inhibitor, and has been shown to be effective in animal models of schizophrenia.
  • triazolopyridines and derivatives thereof are disclosed in WO 2007/113226.
  • Imidazo- and triazolopyridine keratin dyeing compounds are disclosed in US 2005/0229333.
  • Imidazo- and triazolopyridines useful in treating diseases associated with 11-beta-hydroxysteroid dehydrogenase type I are disclosed in WO 2006/135795.
  • Imidazopyridines having phosphatidylinositol 3 kinase inhibitory activity are disclosed in EP 1277754.
  • the present invention provides a novel class of substituted dihydroimidazoisoquinoline PDElO inhibitor compounds and derivatives thereof represented by Formula I, below, pharmaceutical compositions comprising one or more of said compounds of Formula I, and methods of treating PDElO inhibitor mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds of Formula I or pharmaceutical compositions comprising it.
  • CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds of Formula I or pharmaceutical compositions comprising it.
  • Novel compounds of Formula I of the invention have the structural formula:
  • R 1 is R 12 -Ci_ 6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxyalkyl-, -CF 3 or -SF 5 ;
  • R 2 is H, OH, alkoxy, Ci_ 6 alkoxyalkoxy, -OCF 3 , -OSF 5 , -O- C 3 -iocycloalkyl, or -O(CH 2 ) n R;
  • n 0, 1 or 2;
  • R 3 is H, R 12 -Ci_ 6 alkyl, Ci_ 6 alkoxy, C 3 _iocycloalkyl, Ci_ 6 alkoxyalkoxy, OH, -CF 3 , - OCF 3 , -SF 5 , -OSF 5 , halo, -O- C 3 _i 0 cycloalkyl, benzyloxy, -N(R 10 XR 11 ) or CN;
  • R 4 , and R 5 , R 6 , R 7 are independently selected from the group consisting of H, R 12 - Ci_ ⁇ alkyl, R 13 - C ⁇ -ioaryl and R 13 - C 5 _ioheteroaryl; or R 4 and R 5 , together with the carbon atom to which they are attached, form a 3-6 membered carbocyclic ring; or R 6 and R 7 , together with the carbon atom to which they are attached, form a 3-6 membered carbocyclic ring;
  • R 8 is H, R 12 - Ci_ 6 alkyl, C 3 -i 0 cycloalkyl, Ci_ 6 alkoxy, Ci_ 6 alkoxyalkoxy, OH, -CF 3 , - OCF 3 , -SF 5 , -OSF 5 , halo, -O- C 3 _i 0 cycloalkyl, benzyloxy, -N(R 17 ) 2 , CN, R 13 -C 6 _i 0 aryl or R 13 - C 5 _ioheteroaryl;
  • R 9 is R 12 -Ci_ 6 alkyl, R 12 -C 3 _i 0 cycloalkyl, R 13 -C 6 -i 0 aryl, R 13 -C 5 _i 0 heteroaryl or
  • R is selected from the group consisting of
  • R 10 and R 11 are independently selected from the group consisting of H,
  • R 10 and R 11 together with the nitrogen to which they are attached, form a 5 to 7 membered ring, wherein one carbon ring member not adjacent to the nitrogen can optionally be replaced by -O-, -S- or -NR 14 -;
  • R 12 is 1 or 2 substituents independently selected from the group consisting of H, OH,
  • R 13 is 1 or 2 substituents selected from the group consisting of H, halo, Ci_6alkyl, C 2 . galkenyl, OH, hydroxyalkyl, Ci_ 6 alkoxy, CN, -CF 3 , -OCF 3 , -SF 5 , -OSF 5 , -N(R 17 ) 2 ,
  • each R 14 is independently selected from the group consisting of H, Ci_ 6 alkyl, C 3 . iocycloalkyl and C ⁇ -ioarylalkyl;
  • R 15 is 1 or 2 substituents independently selected from the group consisting of H, halo, Ci_ 6 alkyl, Ci_ 6 alkoxy, -CF 3 , C 3 _iocycloalkyl, Ci_ 6 alkoxyalkoxy, OH, hydroxyalkyl, -OCF 3 , -O- C 3 _iocycloalkyl, benzyloxy, -C(O)O C h alky!, -O- Ci_ 6 alkyl-CO 2 H, -C(O)N(R 10 ) 2 , - N(R 10 ) 2 , - Ci_ 6 alkyl-N(R 10 ) 2 , -NR 10 -C(O)N(R 10 ) 2 , -N(R 10 )C(O)O Ci_ 6 alkyl, -N(R 10 )SO 2 - C 1 . ealkyl, phenyl, CN, -SF 5 , -OS
  • R 16 is H, Ci_ 6 alkyl, Ci_ 6 alkoxy
  • each R 17 is independently selected from the group consisting of H, d_ 6 alkyl, C 3 . l ocycloalkyl, C 3 _ioheterocycloalkyl and benzyl.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a
  • the present invention relates to a method of treating PDElO mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
  • CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome
  • administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
  • the invention relates to a method of treating PDElO mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • R 1 is alkyl, preferably methyl.
  • R 2 is H, OH, alkoxy (preferably methoxy or ethoxy) or -O(CH 2 ) n R, preferably -O-CH 2 -quinolyl. More preferably, R 2 is methoxy.
  • -OR 1 and R 2 together form -0-CH 2 -O-.
  • R 3 is H or alkoxy (preferably methyoxy). More preferably, R 3 is H.
  • R 4 , R 5 , R 6 and R 7 are independently H or alkyl; preferably R 4 , R 5 , R 6 and R 7 are each H.
  • R 8 is H, alkyl or aryl; preferably, R 8 is H, alkyl (preferably methyl) or phenyl; more preferably, R 8 is H or methyl.
  • R 9 is R 12 -cycloalkyl, R 13 - C ⁇ -ioaryl or R 13 - C 5 -ioheteroaryl, preferably R 13 - C ⁇ -ioaryl or R 13 - Cs-ioheteroaryl.
  • a preferred R 12 - cycloalkyl group is cyclohexyl.
  • R 13 - C ⁇ -ioaryl groups are R 13 -phenyl, wherein R 13 is H, 1 or 2 alkoxy groups (preferably methoxy), 1 or 2 halo atoms, -OCF 3 , -O-SO 2 -alkyl (preferably -O-SO 2 -methyl), Cs-ioheterocycloalkyl, (preferably
  • R 14 is H or methyl
  • -N(R 17 ) 2 preferably Preferred R 13 -heteroaryl groups are those wherein the heteroaryl portion is thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl or quinolyl; more preferred heteroaryl groups are thiazolyl and pyridyl.
  • R 13 substituents on the carbon atoms of the heteroaryl groups are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl (preferably cyclopropyl), CN, alkenyl (preferably vinyl), hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl),-aminobenzyl, heterocycloalkyl (preferably morpholinyl, pyrrolidinyl or piperidinyl), -alkyl-N(R 10 )(R ⁇ ) (preferably -CH 2 -morpholinyl or -CH 2 -homomorpholinyl), -C(O)N(R 1 ⁇ (R 11 ) (preferably -C(O)-N(alkyl) 2 , -C(O)- morpholinyl,
  • heteroaryl (wherein heteroaryl is preferably pyridyl, imidazolyl, pyrimidinyl or indolyl).
  • Preferred R 13 substituents on the nitrogen atoms of the heteroaryl groups are H, methyl and benzyl, more preferably H.
  • R 9 is R 13 -thiazolyl
  • preferred R 13 substituents are H, 1 or 2 halo atoms, hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl), C 3 _ioheterocycloalkyl, (preferably morpholinyl), -alkyl-N(R 10 )(R ⁇ ) (preferably -CH 2 -morpholinyl or -CH 2 - homomorpholinyl), -C(O)N(R 1 ⁇ (R 11 ) (preferably -C(O)-N(alkyl) 2 , -C(O)-morpholinyl, - C(O)-homomorpholinyl, -C(O)NH-benzyl or
  • R 9 is R 13 -pyridyl
  • preferred R 13 substituents are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl
  • heteroaryl is preferably pyridyl, imidazolyl, pyrimidyl or indolyl.
  • R 1 is alkyl
  • R 2 is H, OH, alkoxy or
  • R 3 is H or alkoxy
  • R 4 , R 5 , R 6 and R 7 are independently H or alkyl
  • R 8 is H, alkyl or aryl.
  • R 1 is alkyl; R 2 is alkoxy; R 3 is H; R 4 , R 5 , R 6 and R 7 are independently H or alkyl; and R 8 is H or alkyl.
  • R 1 is alkyl, preferably methyl; R 2 is alkoxy
  • R 3 is H or alkoxy (preferably methoxy);
  • R 4 , R 5 , R 6 and R 7 are independently H or alkyl, preferably H; and R 8 is H or alkyl, preferably H or methyl.
  • R 9 is preferably R 13 -phenyl; or R 13 -heteroaryl, wherein heteroaryl is preferably thiazolyl or pyridyl; preferred R 13 substituents are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl (preferably cyclopropyl), CN, alkenyl (preferably vinyl), hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl), -aminobenzyl, heterocycloalkyl (preferably morpholinyl, pyrrolidinyl or piperidinyl), -alkyl-N(R 10 )(R ⁇ ) (preferably -CH 2 -morpholinyl or -CH 2 -homomorpholinyl), -C(O)N(R 1 ⁇ (R 11 ) (preferably -C(O)-N(alkyl) (preferably
  • R 1 is methyl, R 2 is methoxy, R 3 to R 7 are H, R 9 is shown by the structure, and R 8 is as defined:
  • R 8 H Preferred compounds of Formula I are those in Examples IA, IB, ID, IE, IH, IN, IP, IQ, IR, IS, IU, IW, IY, IAA, ICC, IFF, IHH, HA, HC, HD, HE, HF, HG, HH, IU, HK, HL, HM, UN, HQ, HR, IIS, IIIA, IIIB, IUC, HID, HIE, IVA, IVB, IVC, IVD, VD, VIA, VIB, VIC, VID, VIE, VIF, VIIA, VIIB, VIIC, VIID, VIIE, VIIF, IX, X, XI, XII, XIV, XXII, XIII, and XXIV.
  • More preferred compounds of Formula I are those in Examples ID, IP, IW, ICC, IFF, HD, HG, IU, HL, HQ, HR, IIIB, IUC, HID, IVD, VIA, VIB, VIC, VID, VIE, VIIA, VIIC, VIID, VIIE, XXII, and XXIV. As used herein, the following terms are as defined below unless otherwise indicated:
  • Mammal means humans and other mammalian animals.
  • alkyl refers to “alkyl” as well as the “alkyl” portions of "hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • Hydroxyalkyl represents an alkyl group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alkyl group.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Halogen represents fluoro, chloro, bromo and iodo.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • isolated or “in isolated form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
  • purified or “in purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantly and the like.
  • Heterocycloalkyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocycloalkyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any - NH in a heterocycloalkyls ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • the heterocycloalkyl ring can be joined to the parent moiety by a ring carbon atom or a ring nitrogen atom.
  • Non-limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl,
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N- substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quina
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • hetero-atom containing ring systems of this invention there are no hydroxyl, halo, amino or thio groups on ring carbon atoms adjacent to a N, O or S.
  • ring carbon atoms adjacent to a N, O or S there are no hydroxyl, halo, amino or thio groups on ring carbon atoms adjacent to a N, O or S.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • variable e.g., alkyl, halo, etc.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs, solvates and co-crystals of the compounds of the invention are also contemplated herein.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 1_4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • a co-crystal is a crystalline superstructure formed by combining an active
  • Co-crystals are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I or II of this invention in different proportions depending on the nature of the co-crystal. (Rmenar, J. F. et. al. JAm. Chem. Soc. 2003, 125, 8456).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective as PDElO inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates,
  • benzenesulfonates bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, co-crystals and prodrugs of the compounds as well as the salts and solvates, co-crystals of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected,
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of Formula I. Isomers may also include geometric isomers, e.g., when a double bond is present.
  • the term "at least one compound of Formula I" means that one to three different compounds of Formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I is used.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Certain isotopically-labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non- isotopically labelled reagent.
  • Compounds of Formula I are prepared by methods known in the art. Typical procedures for preparing the compounds are shown in reaction Schemes 1 and 2; in the schemes, the exemplified compound of Formula I is that wherein R 1 is methyl, R 2 is methoxy, R 3 -R 7 are H and R 8 is H (Scheme 1) or methyl (Scheme 2).
  • Scheme 1 is methyl, R 2 is methoxy, R 3 -R 7 are H and R 8 is H (Scheme 1) or methyl (Scheme 2).
  • Formamide 2 (21 g) was dissolved in dry THF 140 (mL) and cooled to 0 0 C. Et 3 N (70 mL) was added, followed by POCl 3 (10.2 mL in 25 mL of THF) dropwise over 10 min. The reaction was stirred at 0 0 C for 1 h. Ice water (500 mL) was added and the reaction was stirred for 10 min. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO 4 ) and evaporated. The oily residue was purified via column chromatography (25-50% EtOAc/hexanes) to give a colorless oil (17 g), which solidified on standing to a white solid. MS (ESI) 192 (M+H).
  • Example VI-A was prepared according to the procedure outlined for Example IV-A above except that bromide H-J was used in place of bromide H-H.
  • the crude reaction residue was purified via column chromatography (0-5% MeOH-NH 3 /DCM) to give VI-A as a white solid.
  • Example VII-A was prepared according to the procedure outlined for Example V-A above with the exception that bromide H-J was used in place of bromide H-H.
  • the crude reaction residue was purified via column chromatography (0-5% Me0H-NH 3 /DCM) to give VII-A as a white solid.
  • Example IX was prepared according to the procedure outlined for Example VIII above except that bromide H-J (300 mg) was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-10% MeOH-NHs/DCM) to give IX as a white solid (240 mg). LCMS (ESI) 2.84 min (347, M+H).
  • Example XI was prepared according to the procedure outlined for Example X above except that bromide H-J (200 mg) was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-5% MeOH-NHs/DCM) to give XI as a white solid (140 mg). LCMS (ESI) 1.55 min (348, M+H).
  • Example XIII was prepared according to the procedure outlined for Example XII above except that alkene XI (50 mg) was used in place of alkene X. The reaction mixture was filtered through celite and the solvent evaporated to give Example XIII as a white solid (50 mg). LCMS (ESI) 2.55 min (350, M+H).
  • THP ether 9 (73 g) was dissolved in dry THF (700 mL). The solution was cooled to - 78 0 C and stirred at -78 0 C for 20 min. A solution of nBuLi in hexanes (2.5 M, 127 mL) was added slowly. After the addition was complete, the reaction was allowed to stir at -78 0 C for 30 min. B(OMe) 3 (35 mL) was added and the reaction was allowed to warm to ambient temperature over 2 h. IM HCl (600 mL) was added and the reaction vigorously stirred overnight. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were evaporated to a brown oil, and re-dissolved in DCM.
  • Alcohol 13 (19 g) was dissolved in DCM (75 mL) and cooled to 0 0 C.
  • Et 3 N (28 mL) and DMAP (1.5 g) were added, followed by/?-toluenesulfonyl chloride (TsCl) (35 g).
  • TsCl trimethyl methoxylate
  • the reaction was allowed to slowly warm to RT over 2 h.
  • the reaction was cooled to 0 0 C again and water (50 mL) was added and the reaction was vigorously stirred for 1 h at 0 0 C.
  • the layers were separated, and the aqueous layer was extracted with DCM.
  • the combine organic extracts were evaporated and dissolved in acetone (75 mL) and IM NaOH (100 mL) and stirred at ambient temperature overnight.
  • Step 7 Cyclized compound 14 (11 g) was dissolved in DMF (250 niL) and cooled to 0 °C. NBS (8.8 g) was added in one portion and the reaction was stirred at 0 0 C for 2 h. The reaction was diluted with EtOAc and washed with water. The organic phase was dried (MgSO 4 ), and evaporated. The residue was purified via column chromatography (0-10% MeOH/DCM) to give bromide 15 as a white solid (14 g). LCMS (ESI) 2.78 min (338, M+H). Step 8:
  • Example XVIII was prepared according to the general procedure outlined for Example II, except 3-(3-methoxy-phenyl)-propionitrile was used in place of 3-(3,4- dimethoxy-phenyl)-propionitrile (3).
  • Example XIX was prepared according to the general procedure outlined for Example II, except 3-benzo[l,3]dioxol-5-yl-propionitrile was used in place of 3-(3,4-dimethoxy- phenyl)-propionitrile (3).
  • Example XXI was prepared according to the general procedure outlined for Example II, except ammonium benzoate was used in place of ammonium acetate.
  • a typical recommended dosage regimen can range from about 10 mg/dose to about 100 mg/dose, preferably about 10 to about 50 mg/dose, and more preferably about 20 to about 25 mg/dose.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of
  • Liquid form preparations include solutions, suspensions and emulsions.
  • solutions include solutions, suspensions and emulsions.
  • water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacif ⁇ ers for oral solutions, suspensions and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
  • the activity of the compounds of Formula I can be determined by the following procedures.
  • PDElOAl Human recombinant PDElOAl was purchased from BPS Bioscience, Inc. The reaction mixture contained PDElOAl ( 0.02 nM), 10 nM [ 3 H]cAMP ([5 ',8- 3 H] Adenosine 3 ',5 '-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in 50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl 2 , 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 1.
  • the assay was initiated with the addition of substrate and was allowed to proceed for 30 minutes at room temperature before being stopped by the addition of 300 g yttrium SPA PDE beads.
  • the reaction mixtures were thoroughly mixed, and the beads were allowed to settle for 30 minutes.
  • the plates were then counted in a TopCount scintillation counter.
  • Ki values were determined as described by Cheng and Prusoff (1973).
  • VIE VIF, VIIA, VIIB, VIIC, VIID, VIIE, VIIF, IX, X, XI, XII, XIV, XXII, XXIII, and
  • Ki values of less than 10 nM: Examples ID, IP, IW, ICC, IFF, HD, HG, IU, HL, HQ, HR, IIIB, IIIC, HID, IVD, VIA,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des dihydroimidazoisoquinoléines et des dérivés de celles-ci, sur l'utilisation des composés en tant qu'inhibiteurs de phosphodiestérase 10 (PDE10) pour le traitement de troubles modulés par la PDE10, sur des compositions pharmaceutiques comprenant les composés.
PCT/US2010/041122 2009-07-14 2010-07-07 Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10 WO2011008597A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22530609P 2009-07-14 2009-07-14
US61/225,306 2009-07-14

Publications (1)

Publication Number Publication Date
WO2011008597A1 true WO2011008597A1 (fr) 2011-01-20

Family

ID=43449690

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/041122 WO2011008597A1 (fr) 2009-07-14 2010-07-07 Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10

Country Status (1)

Country Link
WO (1) WO2011008597A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014027078A1 (fr) 2012-08-17 2014-02-20 AbbVie Deutschland GmbH & Co. KG Composés inhibiteurs de la phosphodiestérase de type a10
EP2719689A1 (fr) * 2012-10-12 2014-04-16 Les Laboratoires Servier Nouveau procede de synthese du 3-(2-bromo-4,5-dimethoxphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
WO2014079995A2 (fr) 2012-11-26 2014-05-30 Abbvie Inc. Nouveaux composés inhibiteurs de phosphodiestérase de type 10a
WO2014140184A1 (fr) 2013-03-14 2014-09-18 AbbVie Deutschland GmbH & Co. KG Nouveaux composés inhibiteurs de la phosphodiestérase de type 10a
US9388180B2 (en) 2012-09-17 2016-07-12 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
US10039764B2 (en) 2013-07-12 2018-08-07 University Of South Alabama Treatment and diagnosis of cancer and precancerous conditions using PDE10A inhibitors and methods to measure PDE10A expression
WO2021188414A1 (fr) * 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Composés hétérocycliques fonctionnalisés utiles en tant qu'agents antiviraux
US11198693B2 (en) 2018-11-21 2021-12-14 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
WO2021253091A1 (fr) * 2020-06-18 2021-12-23 Alterity Therapeutics Limited Composés et méthodes de traitement de maladies
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11377450B2 (en) 2018-09-21 2022-07-05 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US12011425B2 (en) 2017-08-28 2024-06-18 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051877A1 (fr) * 2001-12-18 2003-06-26 Bayer Corporation 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer
WO2005087919A1 (fr) * 2004-03-12 2005-09-22 Pfizer Products Inc. Structure cristalline de la 3',5'-cyclique nucleotide phosphodiesterase (pde10a) et ses utilisations
WO2009070584A1 (fr) * 2007-11-30 2009-06-04 Wyeth Imidazo[1,5-a]pyrazines fusionnées avec aryle et hétéroaryle en tant qu'inhibiteurs de phosphodiestérase 10

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051877A1 (fr) * 2001-12-18 2003-06-26 Bayer Corporation 2-substitues pyrrolo[2.1-a]isoquinolines contre le cancer
WO2005087919A1 (fr) * 2004-03-12 2005-09-22 Pfizer Products Inc. Structure cristalline de la 3',5'-cyclique nucleotide phosphodiesterase (pde10a) et ses utilisations
WO2009070584A1 (fr) * 2007-11-30 2009-06-04 Wyeth Imidazo[1,5-a]pyrazines fusionnées avec aryle et hétéroaryle en tant qu'inhibiteurs de phosphodiestérase 10

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014027078A1 (fr) 2012-08-17 2014-02-20 AbbVie Deutschland GmbH & Co. KG Composés inhibiteurs de la phosphodiestérase de type a10
US9464085B2 (en) 2012-08-17 2016-10-11 AbbVie Deutschland GmbH & Co. KG Inhibitor compounds of phosphodiesterase type 10A
US9388180B2 (en) 2012-09-17 2016-07-12 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
AU2013237671B2 (en) * 2012-10-12 2017-03-02 Les Laboratoires Servier New process for the synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in the synthesis of ivabradine and additional salts thereof with a pharmaceutically acceptable acid
EP2719689A1 (fr) * 2012-10-12 2014-04-16 Les Laboratoires Servier Nouveau procede de synthese du 3-(2-bromo-4,5-dimethoxphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
AU2013237671A1 (en) * 2012-10-12 2014-05-01 Les Laboratoires Servier New process for the synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in the synthesis of ivabradine and additional salts thereof with a pharmaceutically acceptable acid
FR2996845A1 (fr) * 2012-10-12 2014-04-18 Servier Lab Nouveau procede de synthese du 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
US8779121B2 (en) 2012-10-12 2014-07-15 Les Laboratoires Servier Process for the synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
AU2013237671C1 (en) * 2012-10-12 2017-06-15 Les Laboratoires Servier New process for the synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in the synthesis of ivabradine and additional salts thereof with a pharmaceutically acceptable acid
MD4335C1 (ro) * 2012-10-12 2015-10-31 Les Laboratoires Servier Procedeu de sinteză a 3-(2-bromo-4,5-dimetoxifenil)propannitril şi procedeu de sinteză a ivabradinei şi a sărurilor sale cu utilizarea acestuia
EP2719689B1 (fr) 2012-10-12 2015-12-23 Les Laboratoires Servier Nouveau procede de synthese du 3-(2-bromo-4,5-dimethoxphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
CN103724228B (zh) * 2012-10-12 2016-04-20 瑟维尔实验室 合成3-(2-溴-4,5-二甲氧基苯基)丙腈的新方法以及在合成伊伐布雷定和其与药学上可接受的酸的加成盐中的应用
WO2014057228A1 (fr) * 2012-10-12 2014-04-17 Les Laboratoires Servier Nouveau procede de synthese du -(2-bromo-4,5-dimethoxyphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
CN103724228A (zh) * 2012-10-12 2014-04-16 瑟维尔实验室 合成3-(2-溴-4,5-二甲氧基苯基)丙腈的新方法以及在合成伊伐布雷定和其与药学上可接受的酸的加成盐中的应用
US9790203B2 (en) 2012-11-26 2017-10-17 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
WO2014079995A2 (fr) 2012-11-26 2014-05-30 Abbvie Inc. Nouveaux composés inhibiteurs de phosphodiestérase de type 10a
WO2014140184A1 (fr) 2013-03-14 2014-09-18 AbbVie Deutschland GmbH & Co. KG Nouveaux composés inhibiteurs de la phosphodiestérase de type 10a
US10039764B2 (en) 2013-07-12 2018-08-07 University Of South Alabama Treatment and diagnosis of cancer and precancerous conditions using PDE10A inhibitors and methods to measure PDE10A expression
US12011425B2 (en) 2017-08-28 2024-06-18 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11377450B2 (en) 2018-09-21 2022-07-05 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11198693B2 (en) 2018-11-21 2021-12-14 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11891393B2 (en) 2018-11-21 2024-02-06 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
WO2021188414A1 (fr) * 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Composés hétérocycliques fonctionnalisés utiles en tant qu'agents antiviraux
US11802125B2 (en) 2020-03-16 2023-10-31 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
CN115667256A (zh) * 2020-06-18 2023-01-31 艾特里提治疗有限公司 用于治疗疾病的化合物和治疗疾病的方法
WO2021253091A1 (fr) * 2020-06-18 2021-12-23 Alterity Therapeutics Limited Composés et méthodes de traitement de maladies

Similar Documents

Publication Publication Date Title
WO2011008597A1 (fr) Dérivés de dihydroimidazoisoquinoléine utiles en tant qu'inhibiteurs de pde10
AU2017281228B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
EP3416639B1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1
EP2417135A1 (fr) Triazolopyridines substituées et leurs analogues
EP3319966B1 (fr) Composés hétérocycliques bicycliques utilisés comme inhibiteurs de pde2
EP3534901B1 (fr) Modulateurs allostériques positifs du récepteur muscarinique à l'acétylcholine m4
EP3558309B1 (fr) Modulateurs allostériques positifs du récepteur muscarinique à l'acétylcholine m4
JP2012506873A (ja) 置換ピラゾロキノリンおよびそれらの誘導体
EP3544961B1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
US20240228489A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m1
US20200131180A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m1
EP3534888B1 (fr) Modulateurs allostériques hétéroaryle bicycliques substitués de récepteurs nicotiniques de l'acétylcholine
WO2014194519A1 (fr) Dérivés imidazole et leurs procédés d'utilisation pour l'amélioration des propriétés pharmacocinétiques d'un médicament
US11376254B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US20190330226A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m1
WO2019241467A1 (fr) Modulateurs allostériques positifs du récepteur m1 de l'acétylcholine muscarinique
US10736898B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US12065433B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M1
WO2024086570A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1
WO2024086569A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1
WO2023141511A1 (fr) Modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10800329

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10800329

Country of ref document: EP

Kind code of ref document: A1